When a patent of a small molecule drug expires, generic forms appear on the market. This is also the case for biologics (e.g. monoclonal antibodies, therapeutic proteins, etc.), and we call these biosimilars. These biological 'analogues' are not structurally identical (which is the case for small molecules), but are "highly similar". Given the complexity of the molecular structure of biologics together with their manufacture complexity, it is not possible to manufacture identical molecules or “generics” for biologic agents.

Short explanation on biosimilar and biologics

Thus, a biosimilar is:

- A copy of a biological, which is highly similar to the reference biologic

- It has no clinically meaningful differences in quality, safety and efficacy compared to the reference biologic

For the development of a new biologic agent the clinical trial is similar to the small molecular drugs following a stepwise process. The development of biosimilars is different. This follows a totality-of-the-evidence approach that focuses on physiochemical, biologic and preclinical studies to establish biosimilarity, with clinical development focused on confirming and settling any lingering uncertainties regarding biosimilarity. In order for a biosimilar to be approved by the FDA or EMA, certain requirements must be met. Drug development is focused around 4 steps:

1) Tailoring (analysis of reference product)

2) Fitting (adjustments to the biosimilar to mimic reference)

3) Comparison (in vitro comparing the characteristics)

4) Confirmation (clinical studies to demonstrate PK and PD similarity to the reference product).

The clinical development part of the biosimilar starts with studies to demonstrate comparable pharmacokinetics (PK) and pharmacodynamics (PD) with the reference biologic product in a relevant population. Furthermore, investigations that focus on safety, including immunogenicity, are also implemented early on in clinical development. Hereafter, a minimum of one phase 3 clinical comparability trial is conducted to confirm similar efficacy and safety in a sensitive population. These phase 3 clinical comparability trials are aimed to resolve doubts that remain regarding the efficacy and safety of the biosimilar relative to the reference biologic product following the completion of physiochemical, biologic, preclinical, PK, PD and immunogenicity investigations in human.

Extrapolation

When a biosimilar is approved to be prescribed for all indications for which the original reference product is also registered, it is not necessary that it should have been studied in clinical trials for all these indications. Since it is consided biosimilar, drug trials in the most sensitive population or for the most sensitive disease is suffiicient to extrapolate its use/approval to other indicatiosn. Note that 'most sensitive' is debatable, as the 'sensitivity' of a population or disease is not clearly defined.